Functional response of the rat kidney to inhibition of nitric oxide synthesis: role of cytochrome P450‐derived arachidonate metabolites

Abstract

1 We tested the hypothesis that nitric oxide (NO) exerts a tonic inhibitory in¯uence on cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid (AA). 2 N o -nitro-L-Arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pressure (MBP), from 91+6 to 137+5 mmHg, renal vascular resistance (RVR), from 9.9+0.6 to 27.4+2.5 mmHg ml 71 min 71 , and reduced renal blood¯ow (RBF), from 9.8+0.7 to 6.5+0.6 ml min 71 ) and GFR from 1.2+0.2 to 0.6+0.2 ml 100 g 71 min 71 ) accompanied by diuresis (UV, 1.7+0.3 to 4.3+0.8 ml 100 g 71 min 71 ), and natriuresis (U Na V, 0.36+0.04 to 1.25+0.032 mmol 100 g 71 min 71 ). 3 12, 12 dibromododec-enoic acid (DBDD), an inhibitor of o hydroxylase, blunted L-NAME-induced changes in MBP, RVR, UV and U Na V by 63+8, 70+5, 45+8 and 42+9%, respectively, and fully reversed the reduction in GFR by L-NAME. Clotrimazole, an inhibitor of the epoxygenase pathway of CYP450-dependent AA metabolism, was without e ect. 4 BMS182874 (5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide), an endothelin (ET) A receptor antagonist, also blunted the increases in MBP and RVR and the diuresis/ natriuresis elicited by L-NAME without a ecting GFR. 5 Indomethacin blunted L-NAME-induced increases in RVR, UV and U Na V., an endoperoxide receptor antagonist, attenuated the pressor and renal haemodynamic but not the renal tubular e ects of L-NAME. 6 In conclusion, the renal functional e ects of the CYP450-derived mediator(s) expressed after inhibition of NOS with L-NAME were prevented by inhibiting either CYP450 o hydroxylase or cyclooxygenase or by antagonizing either ET A or endoperoxide receptors. 20-hydroxyeicosatetraenoic acid (20-HETE) ful®ls the salient properties of this mediator.

Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride

“…The importance of NO modulation of 20-HETE synthesis to renal function was evident in the depression of renal hemodynamics and altered sodium excretion produced by disinhibiting 20-HETE formation in response to suppression of NO synthesis by L-NAME (23). The essential findings of this study, that renal microsomal CYP-dependent AA metabolism is enhanced by inhibition of NO synthesis (Table 1), is in accord with our in vivo and in vitro studies.…”

“…The production of 20-HETE is inhibited by NO (10), indicating the importance of NO-CYP interactions to the control of renal function. To underscore the critical nature of NO-CYP interactions, marked perturbations of renal function were produced by inhibiting NOS and thereby eliminating the suppressant effects of NO on 20-HETE synthesis (23). One or more epoxides Renal function is perturbed by inhibition of nitric oxide synthase (NOS).…”

Inhibitors of 20-Hydroxyeicosatetraenoic Acid Reduce Renal Vasoconstrictor Responsiveness

“…In this scheme, inhibition of NO synthesis would increase the formation of 20-HETE to promote smooth muscle contraction. An increase in 20-HETE formation after inhibition of NO synthesis with L-NAME has been implicated in the increases in vascular resistance and blood pressure induced by this agent (Oyekan and McGiff, 1998). Because inhibitors of NO synthesis would also be expected to increase responsiveness to vasoconstrictor agents, the primary aim of the present study was to test the hypothesis that increased synthesis of 20-HETE contributes to the enhanced vasoconstrictor responses observed when NO synthesis is compromised.…”

“…In contrast, removal of this inhibitory effect of NO by NO synthase inhibitors would increase the formation of 20-HETE, which could contribute to the vascular effects of these agents. Thus, inhibition of NOS enhances vascular resistance and increases responses to vasoconstrictor agents (Reid et al, 1991;Oyekan and McGiff, 1998).…”

Nitric oxide modulation of renal and cardiac hemodynamics in type 2 diabetes

“…may explain the impaired glomerular response to L-NMMA infusion (1,32). More particularly, inhibition of endogenous P-450 metabolites of arachidonic acid, such as 20-hydroxyeicosatetraenoic acid as well as other eicosanoids fully reverses the reduction in GFR by N G -nitro-L-arginine-methyl-ester (L-NAME), a compound capable of inhibiting NO synthesis (33). Moreover, eicosanoids contribute to the regulation of renal hemodynamics of several vasoactive peptides, such as endothelin 1 and angiotensin II (34).…”